The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes. We have previously demonstrated that expression of MIF from the primary tumor is required for spontaneous pulmonary metastasis in the 4T1 murine model of breast cancer. MIF is overexpressed in many cancer types, including breast cancer, and the degree of MIF expression correlates with tumor aggressiveness. We therefore sought to understand the link between primary tumor expression of MIF and increased pulmonary metastasis. As a cytokine, we hypothesized that MIF would function by controlling some aspect of the interaction between the tumor and the host immune system. This was supported by our observation that MIF expression was no longer required for metastasis in an immunodeficient SCID/bg host. Using flow cytometry, we discovered that MIF expression in the primary tumor increased the abundance of a subset of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Furthermore, systemic depletion of MDSCs from tumor-bearing mice prevented spontaneous metastasis, suggesting that the MIF-induced increase in MDSCs is likely mediating the enhanced metastasis. Our subsequent observations suggest that MIF and MDSCs may be cooperating not only in the primary tumor, but also at sites of metastasis. Based on these results, we hypothesize that MIF and MDSCs are functioning to promote formation of a “pre-metastatic niche” in the lung. Ongoing studies aim to determine if MIF expression in the primary tumor is actively remodeling lung tissue to promote recruitment and/or differentiation of myeloid cells in the lungs. Metastatic disease is the most common cause of cancer mortality in patients with breast cancer, and gaining a better understanding of how MIF and MDSCs are working to induce metastasis could lead to significant therapeutic advancement for these patients.

Citation Format: Kristen Balogh, Janet Cross. The Macrophage Migration Inhibitory Factor promotes breast cancer metastasis through interaction with the host immune response. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B63.